Novel 3-phenylpropionic acid derivatives for treating diabetes

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

 

The technical field to which the invention relates

The present invention relates to new compounds which are derivatives of 3-phenylpropionic acid, pharmaceutical compositions comprising them and their use for the treatment and/or prevention of diseases and conditions mediated by gamma-receptor proliferator-activator peroxisome (PPARγ). The compounds exhibit the ability to bind to PPARγ receptor and changes in its activity.

The level of technology

More than 20 years ago was open group thiazolidindiones of compounds exhibiting activity on laboratory rodents with type 2 diabetes and insulin resistance. Although the mechanism of action was not known, the connection was successfully used in the treatment of type 2 diabetes. Articles showing that they exert their effects through nuclear PPARγ receptor, were published only in the mid-nineties. Now it is well known that intracellular receptor proteins of the family of PPAR control the expression of genes involved in the regulation of lipid and carbohydrate metabolism.

Diseases such as hyperlipidemia, atherosclerosis, obesity and type 2 diabetes, become a serious problem not only for industrialized countries. It is estimated that more than 150 million people worldwide suffer from type 2 diabetes, and expect the W that this number will double by 2025. In Poland currently about two million people suffer from this disease and the same number at risk of its development. Prices for medical care of patients with diabetes reach 6-8% of the total budget for health care. At the initial stage of diabetes may be asymptomatic and may begin at any age but is most common in middle age and the elderly. The progression of type 2 diabetes is the result of the imposition of such physiological disorders as tissue resistance to insulin, insufficient production of insulin by the pancreas, increased insulin production following increased gluconeogenesis. The most frequent complications of diabetes are microvascular changes in the retina, kidney and nervous system that leads to an increased risk of blindness, kidney failure and nervous system diseases. Diabetes is a major cause of heart attack and stroke.

PPARγ receptors belonging to the family of nuclear receptors that play a role in the regulation of lipid metabolism and deposition. They are expressed in adipose tissue and colon, and involved in the process of lipogenesis. Ligands that activate PPARγ receptors can potentiate the action of insulin and to lower the level of Glu is eskers in the plasma. They can also be useful for the regulation and treatment of disorders of lipid metabolism and energy balance.

Known compounds, which are derivatives or analogs of L-tyrosine, which exert their effects through modulation PRAPγ receptor response, thus acting on glucose metabolism, lipid homeostasis and energy balance.

In international patent applications numbers WO 03/011834 and WO 03/011814 described N-(2-benzoylphenyl)-L-the tyrosine derivatives, which have an activity of partial PPARγ agonist and can be used in treatment and prophylaxis, in particular, disturbed tolerance to insulin, diabetes both type 1 and type 2, dyslipidemia, disorders associated with syndrome X such as hypertension, obesity, insulin resistance, hyperglycemia, atherosclerosis, myocardial ischemia, coronary heart disease, kidney disease, and to improve cognitive function and for treatment of complications caused by diabetes. The described compounds are derivatives of L-tyrosine, in which the hydroxyl group of tyrosine substituted vinyl group and the nitrogen in the amino group of tyrosine substituted 2-benzoylphenyl group.

In international patent application number WO 01/17994 described connection oxazole - PPARγ antagonists that may be useful in the treatment of diabetes, obesity, metabolic the ski syndrome, impaired insulin tolerance, syndrome X and cardiovascular diseases, including dyslipidemia. The compounds are derivatives of L-tyrosine, in which the carboxyl group of tyrosine substituted five-membered heterocycle, hydroxyl group of tyrosine substituted (5-methyl-2-phenyloxazol-4-yl)ethyl group, and the nitrogen of the amino group of tyrosine substituted 2-benzoylphenyl group.

In international patent application number WO 97/31907 described derivatives of 4-hydroxyphenylacetic acids with agonistic activity for PPARγ. Among other described derivatives of L-tyrosine, in which the hydroxyl group of tyrosine substituted five-membered heterocycle which may itself be substituted, and the nitrogen in the amino group of tyrosine substituted disubstituted phenyl group, including 2-benzoylphenyl group.

In the prior art there is still a need for new compounds - PPARγ ligands that can be used in the treatment and/or prevention of diabetes and complications resulting from or associated with diabetes, especially disorders of lipid metabolism and cardiovascular diseases.

The invention

The present invention relates to new compounds which are derivatives of 3-phenylpropionic acid of the formula (I):

where

W is the SON group or its bioisostere, or-COO-C1-C4is an alkyl group;

Y represents NH, N-C1-C10-alkyl, O, or S;

Z is NH, N-C1-C10-alkyl, N-aryl, N-heteroaryl, S, or O;

X represents O, S, NH, N-C1-C10-alkyl, N-aryl, NSO2-C1-C10-alkyl, N-SO2-aryl, or N-SO2-heteroaryl;

R1, R2, R3, R4, R5, R6, R7and R8each independently represents a hydrogen atom or a Deputy selected from the group including

C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, C3-C7-cycloalkane, C1-C4-dialkoxy, C3-C7-cyclotourism, halogen atom, substituted with halogen

C3-C7-cycloalkyl, aryl, heteroaryl, -NO2, -CN, -SO2-NH2, -SO2-NH-C1-C4-alkyl, -SO2-N(C1-C4-alkyl)2, -CO-C1-C4-alkyl, -O-CO-C1-C4-alkyl, -CO-O-C1-C4-alkyl, -CO-aryl, -CO-NH2, -CO-NH-C1-C4-alkyl, -CO-N(C1-C4-alkyl)2;

A represents C1-C4-alkyl, C3-C7-cycloalkyl, substituted with halogen, C3-C7-cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH-CO-C1-C4-alkyl, N(C1-C4-alkyl)-CO-C1-C4-alkyl, -NH-CO-aryl, -N(C1-C4-alkyl)-CO-aryl, -N(C1-C 4-alkyl)-CO-C3-C7-cycloalkyl, -NH-CO-NH2, -NH-CO-NH-C1-C4-alkyl, -NH-CS-NH-C1-C4-alkyl, -NH-CO-NH-aryl, -NH-CS-NH-aryl, -SO2-C1-C4-alkyl, -SO2-aryl, or-SO2-heteroaryl; where the aryl, heteroaryl and heterocyclyl optionally substituted by one or more substituents independently selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy, C1-C4-dialkoxy, Ethylenedioxy, CN, halogen or phenyl, where phenyl optionally substituted by one or more substituents, independently selected from C1-C4-alkyl, C1-C4-alkoxy and halogen atom; and

n represents an integer from 0 to 4 inclusive; and

their pharmaceutically acceptable salts.

One group of compounds according to the invention includes such compounds where W is COOH.

Another group of compounds according to the invention includes such compounds where Y is NH.

Another group of compounds according to the invention includes such compounds, where Y represents O.

Another group of compounds according to the invention includes such compounds where Y is N-C1-C4-alkyl, in particular N-CH3.

Another group of compounds according to the invention includes such compounds where Z represents O.

Another group of compounds according to the invention includes such compounds, Z is S.

Another group of compounds according to the invention includes such compounds where Z represents N-C1-C4-alkyl, in particular N-CH3.

Another group of compounds according to the invention includes such compounds where Z is N-phenyl.

Another group of compounds according to the invention includes such compounds, where X represents O.

Another group of compounds according to the invention includes such compounds, where X is S.

Another group of compounds according to the invention includes such compounds, where X represents the NSO2-C1-C4-alkyl, in particular NSO2-CH3.

Another group of compounds according to the invention includes such compounds where W represents COOH, Y is NH, Z is O and X is O.

Another group of compounds according to the invention includes such compounds where W represents COOH, Y is O, Z is O and X is O.

Another group of compounds according to the invention includes such compounds where W represents COOH, Y is NH, Z is O and X is

NSO2-C1-C4-alkyl, in particular NSO2-CH3.

Another group of compounds according to the invention includes such compounds where W represents COOH, Y is NH, Z is S and X is NSO2-C1-C4-alkyl, in particular NSO2-CH3 .

A particular variant embodiment of the above defined compounds of formula (I) are those compounds where each of the substituents R1- R8represents a hydrogen atom.

Another particular variant embodiment of the above defined compounds of formula (I) are those compounds where n is 1 or 2.

Another group of compounds according to the invention includes such compounds where A is heterocyclyl, which is optionally substituted by one or more substituents independently selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy, C1-C4-dialkoxy, CN, a hydrogen atom and phenyl.

In the above-mentioned group A is preferably isoxazolyl, optionally substituted by one or more substituents, independently selected from C1-C4-alkyl, in particular-CH3.

The next group of compounds according to the invention includes such compounds where A is phenyl, which is optionally substituted, in particular by ethylenedioxythiophene.

The next group of compounds according to the invention includes such compounds where A is-N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, in particular,- N(CH3)-CO-cyclohexyl.

The next group of compounds according to the invention includes such compounds where A is-N(C1-C4-alkyl)CO-heteroaryl, where heteroaryl optionally substituted by one or more substituents independently selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy, C1-C4-dialkoxy, CN, halogen atom, phenyl, and phenyl, optionally replaced by one or more substituents independently selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy and halogen atom.

Preferred heteroaryl is pyrimidinyl, optionally substituted by one or more substituents independently selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy, halogen atom, phenyl, and phenyl optionally replaced by one or more substituents independently selected from the group comprising C1-C4-alkyl, C1-C4-alkoxy and halogen atom.

As examples of specific compounds of the invention may be mentioned the following:

1. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylethoxy)phenyl]propionic acid,

2. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl]propionic acid,

3. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy)phenyl]propionic acid,

4. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[5-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-4-yl]ethoxy)phenyl]propionic sour is a,

5. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(4-{2-[[6-(2-chlorophenyl)-5-cyano-2-(methylthio)pyrimidine-4-yl](methyl)amino]ethoxy})phenyl]propionic acid,

6. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-(2-tert-butyl-5-methyl-1,3-oxazol-4-yl)ethoxy)phenyl]propionic acid,

7. (2S)-2-(1,3-benzothiazol-2-ylamino)-3-[4-(2-(2-tert-butyl-5-methyl-1,3-oxazol-4-yl)ethoxy)phenyl]propionic acid,

8. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]diethoxy)phenyl]propionic acid,

9. (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethylmethanesulfonate)phenyl]propionic acid, and

10. (2S)-2-(1,3-benzoxazol-2-yloxy)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy)phenyl]propionic acid,

and its pharmaceutically acceptable salts.

Compounds according to the invention have a high affinity for gamma receptor proliferator-activator peroxisome (PPARγ). Thus, the compounds show the ability to bind to PPARγ and change its activity.

The invention relates also to pharmaceutical compositions comprising at least one defined above, the compound of formula (I) or its pharmaceutically acceptable salt, optionally in combination with other pharmacologically active ingredients, together with one or more pharmaceutically acceptable carriers and/or excipients is I.

The invention relates also to a certain above compound of formula (I) for use as a medicine.

The invention further relates to the use defined above of compounds of formula (I) or its pharmaceutically acceptable salt for the manufacture of medicinal products for the treatment and/or prophylaxis of diseases and conditions mediated by gamma-receptor proliferator-activator peroxisome (PPARγ).

The invention further relates to a method of treatment and/or prevention of diseases and pathological conditions mediated by gamma-receptor proliferator-activator peroxisome (PPARγ) in need thereof of a mammal, comprising an introduction to the specified mammal defined above of compounds of formula (I) in a therapeutically or prophylactically effective amount.

So, in PPARγ-mediated diseases and pathological conditions include, in particular, disturbed tolerance to insulin, insulin resistance, diabetes type 1 and 2, and complications resulting from or associated with diabetes, such as peripheral neuropathy, renal failure, retinopathy, dyslipidemia, disorders caused by syndrome X such as hypertension, obesity, hyperglycemia, atherosclerosis, myocardial ischemia, coronary heart disease and other cardiovascular is zabolevaniya and kidney disease.

Compounds of the invention may also be useful in improving cognitive functions.

Detailed description of the invention

Definitions

The term “bioisostere”, which is used here, refers to a chemical fragment that replaces another group in the molecule of the active compounds without significant impact on its biological activity. In this case, can be affected by other properties of the active compounds, such as, for example, its stability as a remedy.

As bioisosteric groups to carboxyl (COOH) groups can be, in particular, mentioned 5-membered heterocyclic group having from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, such as, for example, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazole and N-substituted tetrazolyl. 5-membered heterocyclic groups can be optionally substituted by 1 or 2 substituents selected from the group comprising phenyl, pyridinyl, linear or branched alkyl group, amino group, hydroxyl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, triptoreline, cryptorchidectomy, alkoxy, dialkoxy.

As biosante the groups to carboxyl (COOH) groups may be mentioned phenyl and 6-membered heterocyclic group, having from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, such as, for example, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, tetrazines and others. Phenyl and 6-membered heterocyclic groups can be optionally substituted by 1 or 2 substituents selected from the group comprising phenyl, pyridinyl, linear or branched alkyl group, amino group, hydroxyl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, triptoreline, cryptorchidectomy, alkoxy, dialkoxy.

The term “halogen” refers to atoms selected from fluorine atoms, chlorine, bromine and iodine.

The term “alkyl” refers to saturated linear or branched hydrocarbon groups having the specified number of carbon atoms. As a specific alkyl substituents can be mentioned the following: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3,3-dimethylbutyl, heptyl, 1-ethylphenyl, octyl, nonyl and decyl.

The term “aryl” refers to mono - and bicyclic aromatic groups having from 6 to 14 carbon atoms. Examples of aryl groups are phenyl, tolyl, xylyl, naphthyl, such as naphthyl-1-yl, naphthyl-2-yl 1,2,3,4-tetrahedronal-5-yl and 1,2,3,4-tetrahedronal-6-yl.

The term “heteroaryl” refers to mono - and bicyclic heteroaromatic group having from 5 to 13 carbon atoms and from 1 to 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups are pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, 1,3,5-triazinyl, indolyl, benzo[b]furyl, benzo[b]thienyl, indazoles, benzimidazoles, isoindolyl, cannoli, ethenolysis and carbazolyl.

The term “cycloalkyl” refers to a saturated or partially saturated cyclic hydrocarbon group having 3 to 7 carbon atoms. Examples cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl and cycloheptyl.

The term “heterocyclyl” refers to saturated or partially unsaturated 5-, 6-membered cyclic hydrocarbon group having from 1 to 4 heteroatoms selected from N, O and S. Preferably saturated or partially saturated cyclic hydrocarbon is a monocyclic and contains 4 or 5 carbon atoms and 1 to 3 heteroatoms. Examples of heterocyclic groups are piperidinyl, piperazinil, morpholinyl and pyrrolidinyl.

Compounds of the invention contain a chiral center at the carbon atom which kind bearing W group, and can exist in the form of the corresponding enantiomers, mixtures of enantiomers as well as racemic mixtures.

Therefore, R and S enantiomers, mixtures of enantiomers and racemic mixtures of compounds of formula (I) are part of the invention.

Thus, in one variant embodiment of the invention relates to compounds of formula (I)having a stereochemical configuration, such as shown in formula (IA):

where W, X, Y, Z, A, n and R1- R8have the meanings given above for formula (I),

and their pharmaceutically acceptable salts.

In the second variant embodiment of the invention relates to compounds of formula (I)having a stereochemical configuration, such as shown in formula (IB):

where W, X, Y, Z, A, n and R1- R8have the meanings given above for formula (I),

and their pharmaceutically acceptable salts.

The compounds of formula (I), bearing the remainder of the base, can be converted into salts with organic and inorganic acids conventional and known manner by treatment with a suitable acid in an organic solvent, such as alcohol, ketone, ether or a chlorinated solvent, and the extraction of salt in the usual way. Examples of such salts are salts with pharmaceutically p is yimlamai inorganic and organic acids. As examples of salts of inorganic acids may be mentioned the hydrochloride, hydrobromide, nitrate, sulfate, hydrosulfate, persulfate, sulfite, pyrosulfite, phosphate, monohydratefast, dihydrophosphate, metaphosphate and pyrophosphate. As examples of salts of organic acids may be mentioned the acetate, propionate, acrylate, 4-hydroxybutyrate, kaprilat, kapronat, decanoate, oxalate, malonate, succinate, glutarate, adipate, pimelate, maleate, fumarate, citrate, tartrate, lactate, phenylacetate, mandelate, sebacate, suberate, benzoate, phthalate, alkyl - and arylsulfonate, such as methanesulfonate, propanesulfonate, p-toluensulfonate, xylenesulfonate, salicylate, cinnamate, glutamate, aspartate, glucuronate and galacturonic.

The compounds of formula (I)bearing an acid group can be converted into salts with organic and inorganic bases conventional and known manner by reaction of compounds of formula (I) with a suitable organic or inorganic base. Salts with pharmaceutically acceptable bases include salts of alkaline and alkaline-earth metals such as Li, Na, K, Mg or Ca, ammonium salts and salts with basic organic compounds, such as, for example, arginine, histidine, piperidine, morpholine, piperazine, Ethylenediamine or triethylamine, as well as Quaternary ammonium salts.

The present invention is tositsa also to pharmaceutical compositions, includes the compounds of formula (I) with pharmaceutical excipients, depending on the selected route of administration.

One alternative embodiment of the invention are pharmaceutical compositions suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be in the form of tablets, capsules, pills, lozenges, powders, or granules, or solutions, or dispersions in liquids, or the like. Each of the above forms will contain a predetermined quantity of compounds of the invention as an active ingredient. The composition is in the form of tablets can be prepared using any pharmaceutical excipients known in the art for this purpose and is usually used for the preparation of solid pharmaceutical compositions. Examples of such excipients include starch, lactose, microcrystalline cellulose, magnesium stearate and binders, such as polyvinylpyrrolidone. Moreover, the active compound may be included in drug controlled release, such as tablets, comprising a hydrophilic or hydrophobic matrix.

Pharmaceutical composition in the form of capsules can be prepared using conventional methods, for example, through the m introduction mixtures of active compounds and excipients in hard gelatin capsules. On the other hand, can be created and encapsulated in hard gelatin capsules semi-solid matrix active compounds and high molecular weight polyethylene glycol or soft gelatin capsules can be filled with a solution of active compound in polyethylene glycol or its dispersion in food oil. Also discusses powder form for dilution prior to use (e.g., lyophilized powders). On the other hand, for injectable dosage forms can also be used oil fillers.

Liquid forms for parenteral administration may be formulated for administration by injection or continuous infusion.

Acceptable routes of administration by injection is intravenous, intraperitoneal, intramuscular and subcutaneous, and intravenous injections are usually preferred. The usual composition for intravenous administration include sterile isotonic aqueous solution or dispersion comprising, for example, the active substance and dextrose or sodium chloride. Other examples of suitable excipients are the solution of lactate ringer's for injection, the solution of lactate ringer's for injection with dextrose, Normosol-M with dextrose, acylated ringer's solution for injection. Dosage form for injection may optionally includes the ü auxiliary solvent, for example, a polyethylene glycol; a chelating agent such as ethylenediaminetetraacetic acid; a stabilizing agent such as cyclodextrin; and an antioxidant, such as persulfate sodium.

Put the dose will depend on the condition of the patient and the chosen route of administration and will be governed by the doctor.

Compounds of the invention can be obtained using the processes described below and illustrated with examples.

The compounds of formula (I), where W has a value other than-COOH and-COO-C1-C4-alkyl, can be obtained by substitution of a hydrogen atom at X in the molecule of compound (II) A(CH2)ngroup.

where X, Y, Z, A, n, and R1- R8have the meanings defined above for formula (I), and W has a value other than-COOH and-COO-C1-C4-alkyl.

The mentioned substitution may be made by reaction of Mitsunobu described above the compounds of formula (II) with the compound of the formula A(CH2)n-OH, where A and n have the meanings described above, according to the scheme 1

Scheme 1

The reaction Mitsunobu can be carried out in anhydrous solvents, such as ether or substituted with halogen alkane in the presence of diazo compounds, such as DEAD, DIAD, ADDP, and triphenylphosphine, usually in the temperature range from -20 to 20°C.

On the other sides of the, mentioned the substitution of a hydrogen atom when X can be performed by alkylation of compounds of formula (II), where X, Y, Z, and R1- R8have the meanings given above for formula (I), and W has a value other than-COOH and-COO-C1-C4-alkyl, a compound of formula A(CH2)n-V, where A and n have the meanings given above for formula (I), and V is a leaving group selected from halogen and alkylsulfonyl or arylsulfonyl groups, in the presence of a strong base capable of forming the anion of the compound (II), such as, for example, sodium hydride, with the formation of the compounds of formula (I) according to scheme 2

Scheme 2

The alkylation reaction can be carried out in an inert organic solvent, such as anhydrous DMF, THF, DMSO. A strong base capable of forming an anion, which may be sodium hydride. Can be used dry sodium hydride or suspension in mineral oil. The formation of the anion is carried out at room temperature until complete cessation of hydrogen evolution. Next, in a second stage was added alkylating reagent A(CH2)n-V, pure or in solution in an inert organic solvent such as DMF, THF, DMSO. The second stage alkylation is carried out in the temperature range from 0 to 100°C.

Connected to the I according to the invention of formula (I), where W represents-COOH or

-COO-C1-C4-alkyl and X, Y, Z, A, n, and R1- R8have the meanings given above for formula (I)can be obtained by:

a) substitution of a hydrogen atom when X is A(CH2)ngroup in the compound of formula (III)

where R represents a C1-C4is an alkyl group and X, Y, Z, and R1- R8have the meanings given above for formula (I), to form a compound of formula (I), where W represents the ester group-COOR, where R represents a C1-C4is an alkyl group and X, Y, Z, A, n and R1- R8have the meanings given above for formula (I), followed by

b) optional, basic hydrolysis of the ester group-COOR to-COOH groups with the formation of the compounds of formula (I), where W represents-COOH.

The above substitution at the stage a) can be accomplished by the reaction of Mitsunobu the compounds of formula (III) with the compound of the formula A(CH2)n-OH, where A and n have the meanings described above for formula (I), with the formation of the compounds of formula (IV) according to scheme 3

Scheme 3

The above reaction Mitsunobu can be carried out in anhydrous solvents, such as ether or substituted with halogen alkane in the presence of diazo compounds, such as DEAD, DIAD, ADDP, and triphenylphosphine, usually in the intervale temperatures from -20 to 20°C.

On the other hand, the above-mentioned substitution of a hydrogen atom when X can be carried out by reaction of compounds of formula (III), where R represents a C1-C4-alkyl and X, Y, Z, and R1- R8have the meanings given above for formula (I)with the compound of the formula A(CH2)n-V, where A(CH2)nshall have the meaning given above for formula (I), and V represents a leaving group selected from halogen and alkylsulfonyl or arylsulfonyl groups, in the presence of a strong base capable of forming the anion of the compound (III), such as sodium hydride, to form compounds of formula (IV) according to the scheme 4

Scheme 4

The reaction can be carried out, as described above, to obtain compounds of formula (I), where W has a value other than-COOH and-COO-C1-C4-alkyl.

Hydrolysis of the ester group at the stage b) can be carried out in basic conditions known in the technical field method. As examples of the base can be mentioned hydroxides of alkali metals, such as hydroxides of sodium, potassium and lithium. To obtain the individual enantiomers of the compounds of formula (I) is preferable to carry out the hydrolysis with lithium hydroxide, which allows you to save the configuration.

Basic hydrolysis in stage b) can be, for example, providing system, consisting of three solvent is THF (tetrahydrofuran (THF), methanol and water, which allows to obtain a homogeneous reaction mixture. At the end of the hydrolysis, the reaction mixture can be neutralized by hydrochloric acid and, if required, product is in the form of the free acid may be extracted, for example, ethyl acetate according to scheme 5 below:

Scheme 5

The compounds of formula (I), where Y = S and X, W, Z, A, n, and R1- R8have the meanings given above, can be obtained by the reaction of compounds of formula (V), where W, X, A, n and R1- R4have the meanings given above for formula (I)with the compound of the formula (VI), where Z and R5- R8have the meanings given above for formula (I), in the presence of a base in an alcohol solution according to the scheme 6

Scheme 6

In the case of preparing compounds of formula (I), where W represents COOH group, the starting compound in the above-described process is a compound of formula (V), where W is protected COOH group, representing ester as shown in scheme 7. Upon completion of the reaction of the COOH group is released by basic hydrolysis.

According to scheme 7, the first reaction stage, in which the formation of derivatives of ethyl-2-chloro-3-phenylpropionate, sudestada according to the method described Y.Kawamatsu, H.Asakawa, T.Saraie, E.Imamiya, K.Nishikawa, Y.Hamuro, Arzneim. Forsch./Drug Res./, 30(I), 4, 1980, 585-589. Obtained by the reaction of Meerwein chlorine substituted ester reacts with 1,3-benzoxazol-2-thiol in the presence of a base in an alcohol solution, giving the corresponding ethyl α-(1,3-benzoxazol-2-ylthio)ether. Ester hydrolyses in aqueous-alcoholic NaOH or KOH. The free acid is liberated from the salt with dilute hydrochloric acid.

Scheme 7

In a similar way received the following examples of connections:

From optically active starting compounds for the compounds of formula (I) can be obtained in racemic form and in the form of a single enantiomer. On the other hand, racemic compounds of formula (I) can be separated into the enantiomers using conventional techniques known in the field of engineering.

Derivatives of tyrosine of the formula (III), where X = O, Y = NH, and Z = O received according to Shyam B. Advani, Joseph Sam, Journal of Pharmaceutical Sciences, Vol.57, 10, 1968. For example, according to scheme 8 hydrochloride methyl ester of L-tyrosine was obtained by the esterification of L-tyrosine with methanol in the presence of thionyl chloride, followed by reaction of the hydrochloride of the methyl ester of L-tyrosine with 2-chloro-1,3-benzoxazole in benzene in the presence of tree is Ilumina. Similar methods were used in cases of D-tyrosine and D,L-tyrosine.

Scheme 8

The tyrosine compound of formula (III), where X = O, Y = NH, and Z = NH, N-alkyl, N-aryl, N-heteroaryl or S can be obtained by adaptation of the method described above Shyam B. Advani, Joseph Sam, Journal of Pharmaceutical Sciences, Vol.57, 10, 1968.

The tyrosine derivatives of formula (III), where X = O, Y = NH, and Z = S can be obtained according to the method described Edward S. Lazer, Clara K.Miao, Hin Wong Chor, Rondla Sorcek, Denice M. Spero, Alex Galman, Kollol Pal, Mark Behnke, Anne G. Graham, Jane M. Watrous, Carol A. Homon, Juergen Nagle, Arvind Shah, Yvan Guindon, Peter R.Farina, Julian Adams, J.Med.Chem., 1994, 37, 913-923, according to scheme 9

Scheme 9

Derivatives of 4-mercaptoethylamine formula (III), where Y = NH, Z = O and X = S was obtained according to scheme 10, from 4-mercaptoethylamine, which was obtained according to Helen S.M. Lu, Martin Volk, Yuriy Kholodenko, Edward Gooding, Robin M. Hochstrasser, Willian F. DeGrado, Journal of the American Chemical Society, 119, 31, 1997, 7173-7180. Mercaptopropyl (SH) 4-mercaptoethylamine defended trailvoy group, followed by substitution of one hydrogen atom on the nitrogen atom of the α-amino group of 2-benzoxazole. The last stage of synthesis - release SH group.

Scheme 10

Derivatives of 4-aminophenylalanine formula (III), where Y = NH, Z = O and

X = NSO2-CH3received, as shown n the scheme 11, for compounds where X = NSO2-CH3of methyl ester 4-nitro-N-caloifornia. The first stage of the synthesis was performed according to F. Bergel, J.A.Stock, Journal of Organic Chemistry, 1956, 90-96. Thus obtained methyl ester of 4-amino-N-caloifornia was metilirovanie methylchloride in pyridine in the presence of catalytic amounts of DMAP (DMAP). The next stage was to remove falorni group by heating with 6M aqueous hydrochloric acid. Thus obtained 4-methanesulfonylaminoethyl was converted into hydrochloride methyl ester by esterification in methanol in the presence of thionyl chloride. The next stage was the reaction of methyl ester hydrochloride 4-methanesulfonylaminoethyl with 2 chlorobenzoxazole in the presence of triethylamine in benzene

Scheme 11

The initial compounds of the formula (VI), where Z = O, i.e. substituted 2-mercaptobenzoxazole can be obtained according to Roger Lok, Rondla E. Leone, Antony J. Williams, J.Org.Chem., 61, 3289-3297, by the reaction of compounds of formula (VII), where R5- R8have the meanings given above for formula (I)as shown in scheme 12

Scheme 12

The initial compounds of the formula (VIII), i.e. substituted 2-chlorobenzoxazole can be perceived by the s with the use or adaptation of methods, described in Fortuna Haviv, James D. Ratajczyk, Robert W. DeNet, Francis A.Kerdesky, Rolad L.Walters, Steven P. Schmidt, James H. Holmes, Patrick R. Young, George W. Carter, J.Med. Chem., 1988, 31, 1719-1728, by reaction of compounds of formula (VI), where R5- R8have the meanings given above for formula (I), with pentachloride phosphorus according to scheme 13

Scheme 13

Ethyl ester of 3-[4-(benzyloxy)phenyl]-2-hydroxypropionic acid was obtained according to Makoto Takamura, Hiroaki Yanagisawa, Kanai Motoru, Masakatsu Shibasaki, Efficient Synthesis of Antihyperglycemic (S)-α-Aryloxy-β-phenylpropionic Amides Using a Bifunctional Asymmetric Catalyst, Chem. Pharm. Bull., 50, 8, 2002, 1118-1121. Subsequently, the ester was treated with sodium hydride and then with 2-chlorobenzoxazole according to scheme 14

Scheme 14

Here the following abbreviations are used:

DIAD: aminobutiramida azodicarboxylate

DEAD: diethyl-azodicarboxylate

ADDP: azodicarbonamide

EXAMPLES

Example 1

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = NH, n = 1, A = 2,3-dihydro-1,4-benzodioxin-6-yl of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) 2,3-dihydro-1,4-benzodioxin-6-yl-methanol (0.25 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-yl-amino)-3-(4-hydroxyphenyl)propionate (0.31 g, 1 mmol) and triphenyl ospin (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DIAD (and 0.61 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0.1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. The yield is 50%. MC (ES) 446 (M+, 100%).

Example 2

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = NH, n = 1, A = 3.5 dimethylisoxazol-4-yl of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) (3,5-dimethylisoxazol-4-yl)methanol (0.28 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate (0.31 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester named to the slots THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0.1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. An output of 60%. MC (ES) 407 (M+, 100%).

Example 3

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = NH, n = 2, A = (cyclohexylcarbonyl)MediaLingua formula

Was dissolved in 5 ml of tetrahydrofuran (THF) N-(2-hydroxyethyl)-N-methylcyclohexanecarboxylic (0,19 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate (0.31 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added ADDP (0,76 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Further re Klenow mixture was neutralized 1M hydrochloric acid, added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 40%. MC (ES) 465 (M+, 100%).

Example 4

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2-[5-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-4-yl]ethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = NH, n = 2, A = [5-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-4-yl] formula

To a solution of 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethanol (with 2.93 g, 10 mmol) in 30 ml of pyridine was added by portions at room temperature 4-toluensulfonate (1.9 g, 10 mmol). Subsequently, the reaction mixture was stirred for 5 h at room temperature, then poured it into 200 ml of water and was extracted (3×) and 50 ml of dichloromethane. The combined extracts washed with 1M HCl, aqueous sodium bicarbonate solution and saline. In order to receive the product, 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethyl-4-toluensulfonate having a purity of approximately 95%, the organic phase was dried over magnesium sulfate and the solvent was evaporated.

To a solution of 3.12 g of methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate in 50 ml of dimethylformamide was added in portions under stirring at room temperature under argon 60 % suspension of NaH in mi is aralina oil (0.4 g). After cessation of gas evolution was added dropwise a solution of 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethyl-4-toluensulfonate (4,47 g, 10 mmol) in dimethylformamide. The reaction mixture was heated at 80°C and stirring. After cooling, the reaction mixture was poured into 1 l of water and was extracted several times with ethyl acetate. To obtain crude methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[5-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-4-yl]ethoxy)phenyl]propionate, the combined extracts were washed with saline, dried over magnesium sulfate and the solvent was evaporated.

The crude product (2.9 g)obtained above was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 20 ml). Was added 1M LiOH (8 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 40%. MC (ES) 573 (M+, 100%).

Example 5

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(4-{2-[[6-(2-chlorophenyl)-5-cyano-2-(methylthio)pyrimidine-4-yl](methyl)amino]ethoxy})phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = NH, n = 2, A = [6-(2-chlorophenyl)-5-cyano-2-(methylthio)pyrimidine-4-yl](methyl)amino group of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) 4-(2-chlorophenyl)-6-[(hydroxyethyl)(methyl)amino]-2-(methylthio)pyrimidine-5-carbonitrile (0.50 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate (0.31 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 58%. MC (ES) 614 (M+, 100%).

Example 6

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2-(2-tert-butyl-5-methyl-1,3-oxazol-4-yl)ethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = NH, n = 2, A = 2-tert-butyl-5-methyl-1,3-oxazol-4-yl of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) 2-(2-tert-butyl-4-methyl-1,3-oxazol-5-yl)ethanol (0.27 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)is ropionate (0.31 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 55%. MC (ES) 463 (M+, 100%).

Example 7

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]diethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = S, Z = O, Y = NH, n = 2, A = (cyclohexylcarbonyl)(methyl)amino group of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) N-(2-hydroxyethyl)-N-methylcyclohexanecarboxylic (0,19 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate (0.33 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature in ECENA 18-24 hours Subsequently, to obtain the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 46%. MC (ES) 481 (M+, 100%).

Example 8

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethylmethanesulfonate) phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = CH3SO2N, Z = O, Y = NH, n = 2, A = (cyclohexylcarbonyl)(methyl)amino group of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) N-(2-hydroxyethyl)-N-methylcyclohexanecarboxylic (0,19 g, 1.5 mmol), methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-methanesulfonylaminoethyl)propionate (0.39 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in MESI THF/MeOH/H 2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 35%. MC (ES) 542 (M+, 100%).

Example 9

(2S)-2-(1,3-Benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = S, Y = NH, n = 2, A = (cyclohexylcarbonyl)(methyl)amino group of the formula

Was dissolved in 5 ml of tetrahydrofuran (THF) N-(2-hydroxyethyl)-N-methylcyclohexanecarboxylic (0,19 g, 1.5 mmol), methyl (2S)-2-(1,3-benzothiazol-2-ylamino)-3-(4-hydroxyphenyl)propionate (0.33 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid is, added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 48%. MC (ES) 481 (M+, 100%).

Example 10

(2S)-2-(1,3-Benzoxazol-2-yloxy)-3-[4-(2-[(cyclohexylcarbonyl)(methyl)amino]ethoxy)phenyl]propionic acid and its methyl ether

R1- R8= H, W = COOH/COOCH3X = O, Z = O, Y = O, n = 2, A = (cyclohexylcarbonyl)methylaminomethyl formula

Was dissolved in 5 ml of tetrahydrofuran (THF) N-(2-hydroxyethyl)-N-methylcyclohexanecarboxylic (0,19 g, 1.5 mmol), ethyl 2-(1,3-benzothiazol-2-yloxy)-3-(4-hydroxyphenyl)propionate (0.33 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol). The reaction mixture was cooled to 5°C. Then was added DEAD (0.52 g, 3 mmol) and the reaction mixture was stirred at room temperature for 18-24 hours Later to get the product, methyl ester of the above acid THF was evaporated.

The crude product was dissolved in a mixture of THF/MeOH/H2O (6:0,1:1, 2 ml). Was added 1M LiOH (1.6 ml) and stirred the reaction mixture for 3 days at room temperature. Next, the reaction mixture was neutralized 1M hydrochloric acid, was added a small amount of water and the mixture was extracted with ethyl acetate. The solvent was evaporated. The product was purified using chromatography. Yield 40%. MC (ES) 466 (M+, 100%).

Biological the practical tests

The ability of compounds of the invention to contact with the PPAR gamma receptor and alter its activity was determined using the following methods.

Binding in vitro

The ability of compounds to contact the PPAR gamma receptor (in vitro) was determined according to the procedure described below, using the method of competitive exclusion of radioactively labelled ligand from the complex ligand-receptor. As a radioactively labeled ligand used PPAR agonist -3H-rosiglitazone with the final concentration of 10Nm. To the reaction mixture were also added an excess of unlabeled test substances with a final concentration of 20 μm. Source receptor in the test was a human recombinant protein containing the LBD (ligand binding domain) PPAR gamma. The allocation of non-receptor radioactively labelled ligand was performed using dextran-jet method. Radioactivity was measured using a scintillation counter LS 6500-Beckman Coulter. Obtained values of the number of scintillations were compared with the values obtained for the samples incubated with radioactively labeled ligand (assuming a 0% wipe), and with values obtained for samples containing as a radioactively labeled ligand, and the excess is not labeled with a radioactive label rosiglitazone (assuming a 100% displacement). Received zachariadis in the range of 0-130%.

Links:

1. ADD1/SREBP1 activates PPAR gamma through the production of endogenous ligand. Proc. Natl. Acad. Sci. USA. 1998 Apr 14; 95(8): 4333-7.

2. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 1995 Jun 2; 270(22): 12953-6.

3. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA. 1997 Apr. 29; 94(9): 4318-23.

Binding in adipocytes

To confirm the ability of test molecules to contact in vivo, was performed similar experiments using a cell line of mouse fibroblasts 3T3-L1 differentiated adipocytes. Differentiation of fibroblast cells was performed in a 12-hole tablets during the 10-day period. On the day of the experiment cells were washed twice with PBS solution before the one-hour incubation in DMEM containing reference tritium-labeled compound (rosiglitazone) with a concentration of 30 RMB and various concentrations of test substances (concentration ranging from 100 RMB to 20 μm) at 37°C. Then cells were washed three times with PBS solution and was dissolved in 1M NaOH solution. In a prepared as described above, the lysate was measured as radioactively (using scintillation counter LS 6500-Beckman Coulter), and the concentration of protein using the Bradford method). Nonspecific binding was assessed in the presence of unlabeled reference compound (at a concentration of 20 μm).

Received meant is I the number of scintillations were compared with the values obtained for the samples incubated with radioactively labeled ligand (assuming a 0% wipe), and with values obtained for samples containing as a radioactively labeled ligand, and the excess is not labeled with a radioactive label rosiglitazone (assuming a 100% displacement). The obtained values were within the range of 0-130%.

Links:

1. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther. 1998 Feb; 284(2): 751-9.

2. Differential regulation of the stearoyl-CoA desaturase genes by thiazolidinediones in 3T3-L1 adipocytes. J. Lipid Res. 2000 Aug; 41(8): 1310-6.

3. Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARgamma. Mol Cell Biol. 1996 Apr; 16(4): 1567-75.

4. The Differentiation Kinetics ofin vitro3T3-L1 Preadipocyte Cultures. Tissue Eng. 2002 Dec; 8(6): 1071-1081.

5. Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21 (Waf1/Cip1), during adipogenesis. J. Biol. Chem. 1999 Jun 11; 274(24): 17088-97.

Adipokines

Cells cell line 3T3-L1 (ATCC) and maintained in DMEM, supplemented with 10% fetal bovine serum and antibiotics. Two days before the start of the experiment, the cell was transferred into 12-well microplates (30×104of cells per well) and maintained in the next 2 days for the mail merge. After that, the medium was replaced with a mixture of DMEM, FBS and antibiotics and added subjects substances with a final concentration of 50 μm to cells. Under these conditions, the cell which was aged for 14 days, in this environment with tested compounds were changed every 2 days. After 10-14 days, the differentiated cells were photographed with pre-staining oil red O.

Links:

1. Differential regulation of the stearoyl-CoA desaturase genes by thiazolidinediones in 3T3-L1 adipocytes. J. Lipid Res. 2000 Aug; 41(8): 1310-6.

Glucose uptake

Differentiated 3T3-L1 fibroblasts were incubated in DMEM, supplemented with 10% FBS and antibiotics, with subjects substances (at a concentration of 20 μm) for 48 hours thereafter, cells were washed in PBS and then added to the cell-free serum DMEM. Cells were kept in the incubator for 3 h (37°C/5% CO2), and then the medium was replaced KHR buffer solution (25 mm HEPES-NaOH; pH 7,4; 125 mm NaCl; 5 mm KCl; 1.2 mm MgSO4; 1.3 mm CaCl2; 1.3 mm KH2PO4), and cells were incubated for 30 min at 37°C. glucose Uptake was initiated by adding to each test well 50 μm KRH buffer solution containing 0.5 mm 2-deoxy-D-[1,2-3H]glucose (with 0.5 µci) and 100 nm insulin. After 10 min incubation at 37°C the medium was removed and cells were washed three times with ice-cold KRH buffer solution. Then the cells were dissolved in 1M NaOH. In a prepared as described above, the lysate was measured as radioactively (using scintillation counter LS 6500-Beckman Coulter), and the concentration of protein using the Bradford method). Nonspecific binding was assessed in PR is the absence of unlabeled reference compound (at a concentration of 20 μm).

Links:

1. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes. 2002 Jul; 51(7): 2045-55.

2. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther. 1998 Feb; 284(2): 751-9.

3. Identification of bioactive molecules by adipogenesis profiling of organic compounds. J. Biol. Chem. 2003 Feb 28; 278(9): 7320-4. Epub 2002 Dec 19.

4. Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes. J. Biol. Chem. 1985 Mar 10; 260(5): 2646-52.

1. Derivatives of 3-phenylpropionic acid of the formula (I)

where W represents COOH or-COO-C1-C4is an alkyl group;
Y represents NH;
Z represents S or O;
X represents O;
R1-R8each independently represents a hydrogen atom or a halogen atom;
A represents a mono-, bi - or tricyclic 5 to 13-membered heteroaryl with 1 or 2 heteroatoms selected from N, S and O, aryl selected from phenyl and naphthyl, or-N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl where heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of C1-C4-alkyl, CN, halogen, phenyl, and phenyl, optionally substituted with halogen or1-C4-alkoxy; and where the aryl optionally substituted by 1-3 substituents, independently selected from
With1-C4-alkoxy, halogen and Atlantic is gruppy;
n represents an integer from 1 to 3 inclusive;
their pharmaceutically acceptable salts,
provided that the following compounds are excluded:
N-(2-benzothiazolyl)-O-[3-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)propyl]-L-tyrosine,
ethyl N-(2-benzothiazolyl)-O-[3-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)propyl]-L-tyrosine,
N-(benzoxazolyl)-O-[3-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)propyl]-L-tyrosine, and
ethyl-N-(benzoxazolyl)-O-[3-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)propyl]-L-tyrosine.

2. The compound according to claim 1, where W represents COOH.

3. The compound according to claim 1, where Z represents O.

4. The compound according to claim 1, where Z is s

5. The compound according to claim 1, where W represents COOH, Y is NH, Z is O.

6. The compound according to any one of claims 1 to 5, where each of the substituents R1-R8represents a hydrogen atom.

7. The compound according to any one of claims 1 to 5, where n equals 1 or 2.

8. The compound according to claim 1, where a represents isoxazolyl, optionally substituted
C1-C4-alkyl, in particular-CH3.

9. The compound according to any one of claims 1 to 5, where a represents phenyl, which is optionally substituted by ethylenedioxythiophene.

10. The compound according to any one of claims 1 to 5, where a is-N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl.

11. The connection of claim 10, where a is-N(CH3)-CO-cyclohexyl.

12. The compound according to any one of paragraphs.-5, having the stereochemical configuration as shown in formula (IA):

and its pharmaceutically acceptable salts.

13. The compound according to any one of claims 1 to 5, having the stereochemical configuration as shown in formula (IB):

and its pharmaceutically acceptable salts.

14. The compound according to claim 1, selected from the following compounds:
-(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylethoxy)phenyl]propionic acid,
-(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl]propionic acid,
-(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[(cyclohexylcarbonyl)-(methyl)amino]ethoxy)phenyl]propionic acid,
-(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[5-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-4-yl]ethoxy)phenyl]propionic acid,
-(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-(2-tert-butyl-5-methyl-1,3-oxazol-4-yl)ethoxy)phenyl]propionic acid,
-(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-(2-tert-butyl-5-methyl-1,3-oxazol-4-yl)ethoxy)phenyl]propionic acid,
and their pharmaceutically acceptable salts.

15. Pharmaceutical composition having affinity for gamma receptor proliferator-activator peroxisome (PPARγ), comprising the compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt, together with pharmaceutically acceptable carriers and/or vspomogate lname substances.

16. The compound according to any one of claims 1 to 5 for use as a drug that has affinity for gamma receptor proliferator-activator peroxisome (PPARγ).

17. The use of the compounds of formula (I) according to any one of claims 1 to 14 for the manufacture of medicinal products for the treatment and/or prevention of a disease or condition mediated by gamma-receptor proliferator-activator peroxisome (PPARγ).

18. The application 17, where the disease or condition selected from the group consisting of type 2 diabetes, insulin resistance, metabolic syndrome, complications resulting from or associated with diabetes, cardiovascular disorders, atherosclerosis, obesity, cognitive disorders, and disorders of lipid metabolism.

19. The method of treatment and/or prophylaxis of diseases and conditions mediated by gamma-receptor proliferator-activator peroxisome (PPARγ), in need thereof of a mammal, comprising an introduction to the specified mammal the compounds of formula (I) according to any one of claims 1 to 14 in a therapeutically or prophylactically effective amount.
formula (I) according to any one of claims 1 to 14 in a therapeutically or prophylactically effective amount.

20. The method according to claim 19, where the disease or condition selected from the group consisting of type 2 diabetes, resistance to Insa is inu, metabolic syndrome, complications resulting from or associated with diabetes, cardiovascular disorders, atherosclerosis, obesity, cognitive disorders, and disorders of lipid metabolism.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of formula I: , where M is macrolide subunit of substructure II: , L is chain of substructure III: -X1-(CH2)m-Q-(CH2)n-X2-, D is steroid or non-steroid subunit derived from steroid or non-steroid NSAID medicines (nonsteroid anti-inflammatory drug) with anti-inflammatory effect; pharmaceutically acceptable salts and solvates of claimed compounds; methods and intermediary compounds for obtainment of claimed compounds.

EFFECT: improved therapeutic effect, application in inflammatory disease and state treatment for humans and animals.

37 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new 2-pyridone derivatives of formula (I): where R1, R2, R4, R5, G1, G2, L, Y and n are as specified in the invention formula, and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy. These compounds have neutrophil elastase inhibition effect.

EFFECT: new compounds with useful biological properties.

7 cl, 1 tbl, 150 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to the production technology known aminoglycoside antibiotics, in particular to a new method of obtaining isepamicin
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